Breast cancer is a common and often fatal disease. Estrogen frequently plays an important role in sustaining its growth, and therapies aimed at interruption of estrogen action are often useful in treating patients whose tumor contains estrogen receptor (ER). However many estrogen-responsive tumors progress to a more aggressive hormone-independent form; the mechanism of that progression is unknown. The role of other growth factors in regulating breast cancer growth has recently come under study. The presence of the receptor for one such growth factor, the epidermal growth factor (EGF), is inversely correlated with the presence of ER in human breast cancer cell lines and tissue specimens. Its expression in human breast cancer specimens is associated with a poor clinical response. Thus, it is possible that EGF and/or its receptor may be important in regulating breast cancer cell growth and modifying the breast cancer cell's response to estrogen. The studies proposed here will address the hypothesis that over expression of the normal epidermal growth factor receptor (EGFR) or the V-erbB oncogene, which is a truncated form of the EGFR, confers the properties of increased tumorigenicity and hormone independence to hormone- dependent breast cancer cells. ER-positive EGFR-poor MCF-7 human breast cancer cells will be transfected with a vector containing either the human EGFR or v-erbB. Transfected clones will be examined for evidence of 1) down regulation of ER, 2) alteration of mitogenic response to EGF, transforming growth factor alpha (TGF alpha), and 17 beta-estradiol, 3) acquisition of a hormone-independent phenotype as demonstrated by ability to grow in the athymic nude mouse in the absence of estrogen supplementation, 4) enhanced secretion of other polypeptide growth factors which may be important in sustaining growth via autocrine or paracrine pathways, and 5) increased phosphatidyl inositol turnover which is associated with increased EGFR expression in some model systems. Other studies will use anti-sense anti-EGFR oligonucleotide strategies to modulate the level of expression of EGFR in breast cancer cells in order to assess the effects on estrogen response. The identification of potential interactions between the two ligand-receptor systems may provide insight into why anti-estrogen therapies fail and whether or not the EGF/TGF alpha/EGFR system may be a new therapeutic target in breast cancer.